Defensins are small 3-5 kDa cationic endogenous proteins constrained by three disulfide bonds and are primarily known for their antimicrobial activity (Raj P. A. and A. R. Dentino, 2002). Defensins have been shown to be key elements in the innate immune system of many organisms, the first line of defense against invading pathogens. They also act as chemoattractant agents for monocytes and dendritic cells in mammals (Yang et al, 2001). In humans, there are currently six α-defensins, human neutrophil peptides (hNP1 to hNP6) and four β-defensins (hBD1 to hBD4).
As a class of peptides, defensins have broad anti-microbial activity against Gram-negative and Gram-positive bacteria, yeast, and some enveloped viruses including HIV, although specific defensins often have defined spectra of activity (Schroder J. M., 1999). hBD3 has a broad spectrum antimicrobial activity against gram-negative and gram-positive bacteria, fungi, and adenovirus with hBD3 consistently being the most potent. Additionally, hBD3 has significant bactericidal activity against multi-drug-resistant Staphylococcus aureus at physiological salt concentrations (David et al, 2002), and has shown activity against vancomycin-resistant Enterococcus faecium, Burkholderia cepacia and the yeast Candida albicans (Harder et al, 2001; Garcia et al, 2001).
It is generally assumed that the antimicrobial activity of defensins is determined by the existence of an amphiphilic molecular structure and the extent and distribution of cationic and hydrophobic regions on the folded peptide surface (Yeaman and Yount, 2003; Hwang and Vogel, 1998). The presence and the position of disulfide bridges and N-terminal sequence variations/fragments seem to have a marginal influence on the antibacterial effect of β-defensins (Zucht et al, 1998). Only little is known about the influence of structural factors of β-defensins on the interaction with eukaryotic membranes.
Selectivity of effects of antibacterial peptides including β-defensins on bacterial and eukaryotic cells may be determined by the balance of positively charged and hydrophobic surface regions. Disulfide bonds in hBD3, although required for binding and activation of chemokine receptor CCR6 for chemotaxis, appear to be dispensable for its antibacterial function, and a linear structure of [Abu]-hBD3 appears to have abolished the chemotactic activity of hBD3, but the bacterial activity remained unaffected in the absence of any disulfide bond. Despite the significant progress in recent years, the structure-activity relationships for human defensins remain largely unexplored. The sequence rules and structural determinants in human defensins that govern a great variety of biological functions and mechanisms of their action continue to remain poorly understood.
Gordon, Y. Jerold, et al (in Current Eye Research, 2005, 30, 505-15) commented that, among disadvantages, systemic and local toxicity and high manufacturing costs are two major disadvantages for development of antimicrobial peptides as anti-infective drugs. Efforts to develop better defensins have yielded some results suggesting that it is feasible to increase the killing ability, but host cytotoxicity may also increase under these circumstances Accordingly, cytotoxicity may be considered a major challenge for ophthalmic development. Accordingly, there is a need in this field of technology of further investigation and development of effective, improved and less cytotoxic products.